Activation of protein kinases is a central event in cellular signal transduction processes. Aberrant kinase activation is observed in various pathological states. Targeted inhibition of kinases is therefore a fundamental therapeutic aim.
The phosphorylation of proteins is generally initiated by extracellular signals and represents a universal mechanism for controlling various cellular events such as, for example, metabolic processes, cell growth, cell migration, cell differentiation, membrane transport and apoptosis. The kinase protein family is responsible for protein phosphorylation. These enzymes catalyse transfer of phosphate to specific substrate proteins. Based on the substrate specificity, the kinases are divided into two main classes, the tyrosine kinases and the serine/threonine kinases. Both the receptor tyrosine kinases and the cytoplasmic tyrosine and serine/threonine kinases are important proteins in cellular signal transduction. Overexpression or degradation of these proteins plays an important part in disorders based on pathological cell proliferations. These include inter alia metabolic disorders, disorders of the connective tissue and of the blood vessels, and malignant and benign oncoses. In tumour initiation and development they frequently occur as oncogens, i.e. as aberrant, constitutively active kinase proteins. The consequences of this excessive kinase activation are, for example, uncontrolled cell growth and reduced cell death. Stimulation of tumour-induced growth factors may also be the cause of overstimulation of kinases. Development of kinase modulators is therefore of particular interest for all pathogenic processes influenced by kinases.
Pyrido[2,3-b]pyrazine derivatives substituted in position 6 or 7 are widely used as pharmacologically active compounds and as synthons in pharmaceutical chemistry. For example, the patent WO 99/17759 describes pyrido[2,3-b]pyrazines which have in position 6 inter alia alkyl-, aryl- and heteroaryl-substituted carbamates. These compounds are intended to be used to modulate the function of serine-threonine protein kinases.
The patent WO 04/005472 of White et al. describes inter alia pyrido[2,3-b]pyrazines which are carbamate-substituted in position 6 and which, as antibacterial substances, inhibit the growth of bacteria. An antitumour effect is not described.
Certain diphenylquinoxalines and -pyrido[2,3-b]pyrazines with specific alkylpyrrolidine, alkylpiperidine or alkylsulphonamide radicals on a phenyl ring, which may additionally carry urea or carbamate substitutions in position 6 or 7 are described in patents WO 03/084473 (Barnett et al.), WO 03/086394 (Bilodeau et al.) and WO 03/086403 (Lindsley et al.) as inhibitors of the activity of the serine/threonine kinase Akt. Use of these compounds in the treatment of cancers is given. No defined indication of a biological effect is given for the pyrido[2,3-b]pyrazine example compounds described there. Moreover, there is a distinct structural difference to the pyrido[2,3-b]pyrazines according to the invention described in this invention.
In addition, the patent WO 03/024448 of Delorme et al. describes amide- and acrylamide-substituted pyrido[2,3-b]pyrazines which also contain carbamates as additional substituents and can be used as histone deacetylase inhibitors for the treatment of disorders of cell proliferation.
A further publication (C. Temple, Jr.; J. Med. Chem. 1990, 3044-3050) describes in one example the synthesis of a 6-ethyl carbamate-substituted pyrido[2,3-b]pyrazine derivative. An antitumour effect is neither disclosed nor obvious.
The synthesis of further derivatives of 6-ethyl carbamate-substituted pyrido[2,3-b]pyrazine is described in a publication by R. D. Elliott (J. Org. Chem. 1968, 2393-2397). A biological effect of these compounds is neither described nor obvious.
The publication by C. Temple, Jr., J. Med. Chem. 1968, 1216-1218 describes the synthesis and investigation of 6-ethyl carbamate-substituted pyrido[2,3-b]pyrazines as potential antimalarial agents. An antitumour effect is neither disclosed nor obvious.